Benzo-cyclitolamines

ABSTRACT

Compounds having the formula   &lt;IMAGE&gt;   and the pharmaceutically acceptable salts thereof, wherein n is 1 or 2; m is 2, 3 or 4; and R2 is a tertiary amino group; are intermediates useful in the preparation of compounds having hypotensive activity.

This is a division of copending application Ser. No. 888,128, filed Mar.20, 1978 and now U.S. Pat. No. 4,127,717.

BACKGROUND OF THE INVENTION

Various cyclitol derivatives are disclosed in the prior art as havinghypotensive activity. U.S. Pat. No. 3,894,301, issued July 8, 1975,discloses, inter alia, compounds having the formula ##STR2## wherein R₁is as defined hereinafter, X is a bivalent aliphatic radical and Y is anamino group, certain substituted amino groups, or certain nitrogencontaining heterocyclic groups. Compounds having the above formulawherein Y represents certain substituted amino groups not disclosed inthe above referenced patent are disclosed in U.S. Pat. Nos. 3,971,823,issued July 27, 1976 and 4,065,485 issued Dec. 27, 1977.

SUMMARY OF THE INVENTION

Compounds having the formula ##STR3## and the pharmaceuticallyacceptable salts thereof, have useful hypotensive activity. In formulaI, and throughout the specification, the symbols are as defined below.

R₁ is alkanoyl;

R₂ is dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-alkyl-1-piperazinylor 4-morpholinyl;

n is 1 or 2; and

m is 2, 3 or 4.

The term "alkanoyl", as used throughout the specification, refers togroups having 2 to 7 carbon atoms.

The term "alkyl", as used throughout the specification, refers to groupshaving 1 to 6 carbon atoms.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of formula I can be prepared utilizing as a startingmaterial a compound having the formula ##STR4##

Reaction of a compound of formula II with a Grignard reagent having theformula

    R.sub.2 --(CH.sub.2).sub.m --MgX,                          IV

wherein X is a halogen atom, yields an intermediate having the formula##STR5## The reaction can be run in an organic solvent such astetrahydrofuran, at the reflux temperature of the solvent. Conveniently,the Grignard reagent of formula IV can be formed in situ by mixingmagnesium and an aminoalkylhalide having the formula

    R.sub.2 --(CH.sub.2).sub.m --X,                            VI

wherein X is a halogen atom. In some instances it may be necessary toadd a dihaloalkylene compound to initiate the reaction.

Reaction of a compound of formula III with a compound of formula VIyields an intermediate having the formula ##STR6## The reaction is runin the presence of a proton removing agent such as sodium amide and canbe run in a mixture of an organic solvent, e.g., ether, and liquidammonia.

When an intermediate of either formula V or VII is subjected to a Birchreduction, the resultant diene intermediate will have the formula##STR7## The well-known Birch reduction comprises the reduction of anaromatic compound using ammonia and a metal. For the reduction of anaromatic compound of formula V or VII it has been found effective toutilize lithium ribbon as the metal.

Oxidation of a diene intermediate of formula VIII yields a tetrolderivative having the formula ##STR8## The oxidation can be accomplishedby treating a diene of formula VIII with formic acid and hydrogenperoxide followed by basic hydrolysis. The tetrols of formula IX arenovel intermediates; and as such, they constitute an integral part ofthis invention.

A tetrol intermediate of formula IX can be converted into thecorresponding product of formula I by reaction with the appropriate acidanhydride ((R₁ CO)₂ O) in the presence of an acid catalyst such asperchloric acid.

The compounds of formula I contain five asymmetric centers; i.e., thefour carbon atoms to which are attached the R₁ O-- groups and the carbonatom to which is attached the R₂ --(CH₂)_(m) -- group. In the preferredembodiment of this invention, the R₁ O-- groups are axially oriented andthe fusion of the two aliphatic rings is, therefore, trans. The R₂--(CH₂)_(m) -- group can be oriented either cis or trans to the closestR₁ O-- group. The compounds exist as racemic mixtures and can beseparated into their optical isomers using conventional techniques.

The compounds of formula I are useful for the treatment of hypertensionin mammals. For this purpose, they can be administered in daily doses offrom 5 to 50 milligrams per kilogram of body weight; preferably about 5to 25 milligrams per kilogram of body weight can be administered insingle or divided doses.

The compounds of the present invention can be administered orally, forexample, with an inert diluent or with an assimilable edible carrier, orthey can be enclosed in hard or soft gelatin capsules, or they can becompressed into tablets, or they can be incorporated directly with thefood of the diet. For oral therapeutic administration, the activecompounds of this invention can be incorporated with excipients and usedin the form of tablets, troches, capsules, elixirs, suspensions, syrups,wafers, chewing gum, and the like. Such compositions and preparationsshould contain at least 0.1% of active compound. The percentage in thecompositions and preparations can, of course, be varied and canconveniently be between about 5% to about 75% or more of the weight ofthe unit. The amount of active compound in such therapeutically usefulcompositions or preparations is such that a suitable dosage will beobtained. Preferred compositions or preparations according to thepresent invention are prepared so that an oral dosage unit form containsbetween about 5 to 250 milligrams of active compound.

The following examples are specific embodiments of this invention.

EXAMPLE 12,3:4a,11a-trans-5-[3-(Dimethylamino)propyl]-1,2,3,4,10,11-hexahydro-5H-dibenzo[a,d]cycloheptene-2,3,4a,11a-tetrol,tetraacetate ester (A)5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenzo-[a,d]cyclohepten-5-ol

3-(Dimethylamino)propyl chloride (110 g) is dissolved in 600 ml oftetrahydrofuran. About 10% of this solution is added to the reactionflask containing 26.4 g of magnesium and 50 ml of tetrahydrofuran. Themixture is heated to reflux and reaction is initiated with ethylenedibromide. The remaining halide is added slowly (over about 30 minutes)to control the rate of reflux. The mixture is then heated under refluxfor an additional 30 minutes. After cooling in an ice bath, 100 g ofdibenzosuberone in 200 ml of tetrahydrofuran is added slowly (over about30 minutes). The mixture is heated under reflux for 1.5 hours. Aftercooling in an ice bath, the mixture is decomposed by dropwise additionof saturated ammonium chloride solution (1 liter added in 2 hours). Themixture is stirred for an additional hour, the layers are separated andthe aqueous layer is reextracted with ether. The combined organic layersare dried over magnesium sulfate, filtered and the solvent is removed invacuo. The residue is dissolved in ether and extracted with 10%hydrochloric acid. The aqueous layer is basified with sodium hydroxideand extracted twice with ether. The ether extracts are dried, filtered,and the solvent is removed in vacuo leaving 103 g of a solid.

(B)4,5,10,11-Tetrahydro-N,N-dimethyl-1H-dibenzo[a,d]cycloheptene-5-propanamine

5-[3-(Dimethylamino)propyl]-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-ol(50.2 g) is partially dissolved in 350 ml of ether and added to 2 litersof liquid ammonia. Lithium ribbon (4.73 g) is then added portionwiseover a period of 15 minutes. After stirring for 20 minutes, absolutealcohol is added dropwise until the color is discharged (about 90 mladded over a period of 1 hour). More ether is added and the ammonia isboiled off. While cooling in an ice bath the mixture is diluted slowlywith 1 liter of water. The layers are separated and the aqueous layer isreextracted with ether. The combined organic layers are dried overpotassium carbonate, filtered, and the solvent is removed in vacuo,leaving 47.0 g of an oil. NMR indicates this is about 50% of the desireddiene (the bulk of remaining material being unreduced startingmaterial).

(C)2,3:4a,11a-trans-5-[3-(Dimethylamino)propyl]-2,3,4,5,10,11-hexahydrodibenzo[a,d]cycloheptene-2,3,4a,11a-tetrol

Crude4,5,10,11-tetrahydro-N,N-dimethyl-1H-dibenzo-[a,d]cycloheptene-5-propanamine(47 g) is added slowly to 200 ml of cold 88% formic acid. Hydrogenperoxide (80 ml of 30%) is added dropwise over a period of 30 minutes ata temperature below 35° C. After addition is complete, the temperatureis allowed to rise to 50° C. and held at 40°-50° C. for 1 hour beforethe mixture is left stirring for about 16 hours in a water bath at roomtemperature. The mixture is taken to near dryness in vacuo. Water isadded twice and removed in vacuo (negative to starch-potassium iodidepaper after second addition). The viscous residue is dissolved in 200 mlof ethanol, cooled in an ice bath and treated with a solution of 70 g ofpotassium hydroxide in 80 ml of water. After heating for 30 minutes on asteam bath, the mixture is diluted to about 600 ml with ice water. Fourether extractions yield 47.8 g of viscous material which fails tocrystallize. This is chromatographed on 1 kg of Activity IV basicalumina. The tetrol product is eluted with chloroform and 2% methanol inchloroform. Fractions weighing 12.8 g are primarily the contaminatedtetrol. The material fails to crystallize.

(D)2,3:4a,11a-trans-5-[3-(Dimethylamino)propyl]-1,2,3,4,10,11-hexahydro-5H-dibenzo[a,d]cycloheptene-2,3,4a,11a-tetrol,tetraacetate ester

2,3:4a,11a-trans-5-[3-(Dimethylamino)propyl]-1,2,3,4,10,11-hexahydro-5H-dibenzo[a,d]cycloheptene-2,3,4a,11a-tetrol(2.4 g) is dissolved in 25 ml of acetic anhydride and 1 ml of glacialacetic acid. The solution is cooled to -40° C. and 2 ml of 70%perchloric acid is added dropwise. The mixture is stored for about 16hours at -12° C. After cooling to -30° C., 13 ml of methanol is addeddropwise over a period of 30 minutes. The mixture is poured into 75 mlof cold concentrated ammonium hydroxide. The product is extracted intochloroform, filtered, and the solvent is removed in vacuo leaving 3.0 gof foam. Hexane is added and 1.6 g of crystalline material is deposited.This is recrystallized from ethyl acetate-hexane to give 1.17 g of thetitle compound, melting point 193°-197° C. (shrinking occurs at 186°C.).

Anal. Calc'd. for C₂₈ H₃₉ O₈ N: C, 64.97; H, 7.60; N, 2.71. Found: C,65.23; H, 7.81; N, 2.61.

EXAMPLE 22,3:4a,9a-trans-9-[3-(Dimethylamino)ethyl]-1,2,3,4,4a,9,9a,10-octahydro-2,3,4a,9a-anthracenetetrol,tetraacetate ester (A) 9,10-Dihydro-N,N-dimethyl-9-anthracenepropanamine

Sodium amide is prepared in 1.5 liters of liquid ammonia from 23 g ofsodium and a slurry of 90.1 g (0.5 M) of 9,10-dihydroanthracene in 400ml of ether is added. A solution of 36.2 g of 3-(dimethylamino)propylchloride in 60 ml of ether is added steadily in 3 minutes. Afterstirring for 1 hour, solid ammonium chloride is added in 15 minutes.More ether is added and the ammonia is boiled off. The solids areremoved by filtration and washed with ether, and the filtrate is driedand taken to dryness in vacuo. The sample is redissolved in ether andthe basic material is extracted into dilute hydrochloric acid. Theacidic aqueous layer is washed twice with ether and basified. Theproduct is extracted into ether, dried and freed of solvent leaving 68.2g of the title compound.

(B) 1,4,9,10-Tetrahydro-N,N-dimethyl-9-anthracenepropanamine

A solution of 21.55 g of9,10-dihydro-N,N-dimethyl-9-anthracenepropanamine in 100 ml of ether isadded to 1 liter of liquid ammonia. Lithium ribbon (1.125 g) is added inseveral portions over a period of 5 minutes. After stirring for 15minutes, absolute ethanol is added dropwise until the color isdischarged (25 ml added in 30 minutes). More ether is added and theammonia is boiled off. The mixture is then cooled in an ice bath and 500ml of water is added. The layers are separated and the aqueous layer isreextracted with ether. The combined ether layers are dried overpotassium carbonate, filtered, and the solvent is removed in vacuoleaving 21.2 g of crude product.

(C)9-[3-(Dimethylamino)propyl]-1,2,3,4,4a,9,9a,10-octahydro-2,3,4a,9a-anthracenetetrol

Crude 1,4,9,10-tetrahydro-N,N-dimethyl-9-anthracenepropanamine is addedslowly to 100 ml cold 88% formic acid. Hydrogen peroxide (40 ml of 30%)is then added dropwise over a period of 1 hour maintaining thetemperature below 35° C. After addition is complete, the temperature isheld at 35°-45° C. for 3 hours before the mixture is left for about 64hours in a water bath at room temperature. The mixture is taken to neardryness in vacuo. Water is added (negative to starch-potassium iodidepaper) and removed in vacuo. The residue is dissolved in 100 ml ofabsolute ethanol and, while cooling, is treated with a solution of 36 gof potassium hydroxide in 40 ml of water. After heating on a steam bathfor 30 minutes, the mixture is diluted to 300 ml with ice water. Fourether extractions give 22.6 g viscous material which fails tocrystallize and is chromatographed on 500 g of Activity IV basicalumina. Fractions eluted with 2% methanol in chloroform contains thetetrol which crystallizes on standing in ether. A total of 7.3 g ofcrystalline tetrol product is obtained. A 3.0 g sample wasrecrystallized from ethyl acetate with charcoal decolorization to give0.9 g of the title compound, melting point 168°-176° C. (shrinkingoccurs at 160° C.).

(D)2,3:4a,9a-trans-9-[3-(Dimethylamino)ethyl]-1,2,3,4,4a,9,9a,10-octahydro-2,3,4a,9a-anthracenetetrol,tetraacetate ester

9-[3-(Dimethylamino)propyl]-1,2,3,4,4a,9,9a,10-octahydro-2,3,4a,9a-anthracenetetrol(2.1 g) is dissolved in 25 ml of acetic anhydride and 1 ml of glacialacetic acid. The solution is cooled to -40° C. and 2 ml of 70%perchloric acid is added dropwise. The mixture is kept for about 16hours at -12° C. After cooling to -30° C., 13 ml of methanol is addeddropwise over a period of 20 minutes. The mixture is then poured into 75ml of cold concentrated ammonium hydroxide, and immediately extractedtwice with chloroform. The chloroform extracts are dried over magnesiumsulfate, filtered, and the solvent is removed in vacuo leaving 2.8 g ofviscous material. Hexane is added and some crystalline material isdeposited. This is harvested and recrystallized from hexane-ether togive 270 mg of the title compound, melting point 168°-172° C. (shrinkingoccurs at 150° C.).

Anal. Calc'd. for C₂₇ H₃₇ O₈ N: C, 64.39; H, 7.41; N, 2.78. Found: C,64.42; H, 7.29; N, 2.54.

EXAMPLES 3-8

Following the procedure of Example 1, but substituting the compoundlisted in column I for 3-(dimethylamino)propyl chloride, yields thecompound listed in column II.

    ______________________________________                                        Column I         Column II                                                    ______________________________________                                        2-(dimethylamino)ethyl                                                                         2,3:4a,11a-trans-5-[2-                                       chloride         (dimethylamino)ethyl]-1,2,3,-                                                 4,10,11-hexahydro-5H-di-                                                      benzo[a,d]cycloheptene-                                                       2,3,4a,11a-tetrol, tetra-                                                     acetate ester                                                4-(diethylamino)butyl chloride                                                                 2,3:4a,11a-trans-5-[4-(di-                                                    ethylamino)butyl]-1,2,3,4,-                                                   10,11-hexahydro-5H-dibenzo-                                                   [a,d]cycloheptene-2,3,4a,11a-                                                 tetrol, tetraacetate ester                                   1-(2-bromoethyl)pyrrolidine                                                                    2,3:4a,11a-trans-5-[2-(1-                                                     pyrrolidinyl)ethyl]-1,2,3,-                                                   4,10,11-hexahydro-5H-di-                                                      benzo[a,d]cycloheptene-                                                       2,3,4a,11a-tetrol, tetra-                                                     acetate ester                                                1-(3-bromopropyl)piperidine                                                                    2,3:4a,11a-trans-5-[3-(1-                                                     piperidinyl)propyl]-1,2,3,-                                                   4,10,11-hexahydro-5H-di-                                                      benzo[a,d]cylcoheptene-                                                       2,3,4a,11a-tetrol, tetra-                                                     acetate ester                                                1-(4-bromobutyl)-4-methyl-                                                                     2,3:4a,11a-trans-5-[4-(4-methyl-1-                           piperazine       piperazinyl)butyl]-1,2,3,4,-                                                  10,11-hexahydro-5H-dibenzo-                                                   [a,d]cycloheptene-2,3,4a,11a-                                                 tetrol, tetraacetate ester                                   4-(2-bromoethyl)morpholine                                                                     2,3:4a,11a-trans-5-[2-(4-                                                     morpholinyl)ethyl]-1,2,3,4,-                                                  10,11-hexahydro-5H-dibenzo-                                                   [a,d]cycloheptene-2,3,4a,11a-                                                 tetrol, tetraacetate ester                                   ______________________________________                                    

EXAMPLES 9-15

Following the procedure of Example 2, but substituting the compoundlisted in column I for 3-(dimethylamino)propyl chloride, yields thecompound listed in column II.

    ______________________________________                                        Column I        Column II                                                     ______________________________________                                        2-(dimethylamino)ethyl                                                                        2,3:4a,9a-trans-9-(2-dimethylamino-                           chloride        ethyl)-1,2,3,4,4a,9,9a,10-                                                    octahydro-2,3,4a,9a-anthra-                                                   cenetetrol, tetraacetate ester                                3-(di-n-hexylamino)propyl                                                                     2,3:4a,9a-trans-9-[3-(di-n-hexyl-                             chloride        amino)propyl]-1,2,3,4,4a,9,9a,-                                               10-octahydro-2,3,4a,9a-anthra-                                                cenetetrol, tetraacetate ester                                4-(diisopropylamino)butyl                                                                     2,3:4a,9a-trans-9-[4-(diiso-                                  chloride        propylamino)butyl]-1,2,3,4,4a,-                                               9,9a,10-octahydro-2,3,4a,9a-                                                  anthracenetetrol, tetraacetate                                                ester                                                         1-(3-bromopropyl)pyrroli-                                                                     2,3:4a,9a-trans-9-[3-(1-                                      dine            pyrrolidinyl)propyl]-1,2,3,-                                                  4,4a,9,9a,10-octahydro-2,3,-                                                  4a,9a-anthracenetetrol, tetra-                                                acetate ester                                                 1-(4-bromobutyl)piperidine                                                                    2,3:4a,9a-trans-9-[4-(1-                                                      piperidinyl)butyl]-1,2,3,4,-                                                  4a,9,9a,10-octahydro-2,3,4a,-                                                 9a-anthracenetetrol, tetra-                                                   acetate ester                                                 2-(2-bromoethyl)-4-methyl-                                                                    2,3:4a,9a-trans-9-[2-(4-methyl-                               piperazine      1-piperazinyl)ethyl]-1,2,3,-                                                  4,4a,9,9a,10-octahydro-2,3,4a,-                                               9a-anthracenetetrol, tetra-                                                   acetate ester                                                 4-(3-bromopropyl)morpho-                                                                      2,3:4a,9a-trans-9-[3-(4-                                      line            morpholinyl)propyl]-1,2,3,4,-                                                 4a,9,9a,10-octahydro-2,3,-                                                    4a,9a-anthracenetetrol, tetra-                                                acetate ester                                                 ______________________________________                                    

What is claimed is:
 1. A compound having the formula ##STR9## wherein R₂is dialkylamino, 1-pyrrolidinyl, 1-piperidinyl, 4-alkyl-1-piperazinyl or4-morpholinyl; n is 1 or 2; and m is 2, 3 or 4 wherein the term "alkyl"refers to groups having 1 to 6 carbon atoms.
 2. A compound in accordancewith claim 1 wherein the hydroxyl groups are axially oriented.
 3. Acompound in accordance with claim 1 wherein R₂ is dialkylamino.
 4. Acompound in accordance with claim 3 wherein R₂ is dimethylamino.
 5. Acompound in accordance with claim 1 wherein R₂ is 1-pyrrolidinyl,1-piperidinyl, 4-alkyl-1-piperazinyl or 4-morpholinyl.
 6. A compound inaccordance with claim 1 wherein n is
 1. 7. A compound in accordance withclaim 1 wherein n is
 2. 8. A compound in accordance with claim 1,2,3:4a,11a-trans-5-[3-(dimethylamino)propyl]-2,3,4,5,10,11-hexahydrodibenzo[a,d]cycloheptene-2,3,4a,11a-tetrol.9. A compound in accordance with claim 1,9-[2-(dimethylamino)propyl]-1,2,3,4,4a,9,9a,10-octahydro-2,3,4a,9a-anthracenetetrol.